Table 2 Barriers to interconversion between conformers of the cyclophanes 5 and 6
Equilibration
between…
Ratio
at 298 K
n
R
DG°a/kJ mol21
DGf‡a/kJ mol21
DGb‡a/kJ mol21
t1a,b
2
5a
6a
6c
6d
6
6
8
9
H
anti " ent-anti
anti " ent-anti
anti " ent-anti
anti " syn
50 : 50c,d
50 : 50c,g
50 : 50c,g
42 : 58i
0
0
0
36.6e
> 90
> 90
70.8j
36.6e
> 90
< 0.3 msf
> 10 minh
> 10 minh
290 ms
Me
Me
Me
> 90
20.82
71.7j
‡
DH° = 25.1 kJ mol21
DHf‡ = 68.9 kJ mol21
DHb = 74.0 kJ mol21
DS° = 214.1 J mol21 K21 DSf‡ = 26.5 J mol21 K21 DSb = 7.6 J mol21 K21
‡
6e 10 Me
anti " syn
anti " syn
64 : 36i
35 : 65i
1.5
66.6j
65.1j
50 ms
‡
DH° = 24.4 kJ mol21
DHf‡ = 66.7 kJ mol21
DHb = 71.1 kJ mol21
DS° = 220.0 J mol21 K21 DSf‡ = 0.2 J mol21 K21
DSb = 20.2 J mol21 K21
‡
7
—
Me
21.5
51.5j
53.0j
< 0.12 ms
a At 298 K. b Of the anti conformer. c Symmetry demands a 50 : 50 ratio of enantiomeric anti conformers. d Molecular modelling (B3LYP/6-31G*) suggests
that the syn conformer is at least 20 kJ mol21 less stable. e Determined by variable temperature NMR in CD2Cl2. DG‡ is given at the coalesence temperature
(203 K). f On the assumption that DS‡ is small. g Integration of the 500 MHz 1H NMR spectrum revealed a > 99 : < 1 mixture of anti and syn conformers.
h The enantiomeric anti conformers were resolved by chiral analytical HPLC. i Ratio of the anti and syn conformers determined by integration of the 500
MHz 1H NMR spectrum. j Determined by comparison of simulated spectra, generated using gNMR,5 with experimental spectra recorded at several
temperatures in d8-toluene.
min),6 and, hence, that the barrier to racemisation was at least 90 kJ
mol21
tether. The half lifes, t , of the anti conformers of the [2.n]
1
2
.
metacyclophanes 6 increase from 50 ms (with n = 10) to 290 ms
(with n = 9) to greater than 10 min (with n 5 8).
We thank EPSRC for funding, Julie Fisher, Steve Homans and
Stuart Warriner for helpful discussions, Simon Barrett for vt-NMR
experiments, Jacqueline Colley for HPLC analyses and Andrew
Leach for molecular modelling.
The tether had a smaller effect on the configurational stability of
the cyclophanes 6 than did the indolyl 2-methyl groups. The barrier
to isomerisation of the anti conformer of the bisindolylmaleimide 7,
in which the tether had been removed, was 51.5 kJ mol21; in
contrast, the barrier to racemisation of 5a, in which R = H, was just
36.6 kJ mol21
.
Notes and references
† gNMR was used to produce simulated spectra based on populations of the
syn and anti conformers extrapolated from the slow exchange regime.
‡ The cyclophanes 6a–c exclusively ( > 95 : 5) populated the chiral (anti)
conformer.
1 For a review see: U. T. Rüegg and G. M. Burgess, Trends Pharm. Sci.,
1989, 10, 218.
There is a substituent in each of the ortho positions flanking each
[3,3A]bipyrrolyl bond of 7 (the bipyrrolyl unit is shown in black);
given that tetrasubstituted biphenyls 8 (A ≠ B ≠ H; C ≠ D ≠ H)
are generally resolvable,7 it is, perhaps, surprising that the
conformers of bisindolylmaleimides such as 7 are not atropisomers.
However, the internal bond angles of a biphenyl8 (119°) are
markedly wider than those of a bisindolylmaleimide9 (107° and
108° in the crystal structure of 3), so the carbons which are ortho to
the bipyrrolyl bond are further apart (2.96 and 3.30 Å8) than for
biphenyl7 (2.92 Å). In addition, small size of the maleimide oxo
group can be rivalled by only a hydrogen atom (compare the length
of its carbonyl bond, 1.21 Å, with bonds to other “small”
substituents:7 1.39 Å for Ph–F, 1.45 Å for Ph–OH). Furthermore,
conjugation between a maleimide and an indole in the transition
state is far more stabilising than conjugation between two phenyl
rings.
In summary, the addition of indolyl 2-methyl substituents to
bisindolylmaleimides such as 3 is not sufficient for configurational
stability. The effect of indolyl 2-methyls may be exaggerated by the
presence of a tether between the nitrogen atoms of the indoles
(?6). Like other metacyclophanes,10 the activation energy for
interconversion between limiting conformers (anti and syn con-
fomers in this case) is critically dependent on the length of the
2 R. A. Bit, P. D. Davis, L. H. Elliott, W. Harris, C. H. Hill, E. Keech, G.
Kumar, A. Maw, J. S. Nixon, D. R. Vessey, J. Wadsworth and S. E.
Wilkinson, J. Med. Chem., 1993, 36, 21; D. Toullec, P. Pianetti, H.
Coste, P. Bellevergue, T. Grand-Perret, M. Ajakane, V. Baudet, P.
Boissin, E. Boursier, F. Loriolle, L. Duhamel, D. Charon and J.
Kirilovsky, J. Biol. Chem., 1991, 266, 15771.
3 M. R. Jirousek, J. R. Gillig, C. M. Gonzalez, W. F. Heath, J. H.
McDonald III, D. A. Neel, C. J. Rito, U. Singh, L. E. Stramm, A.
Melikian-Badalian, M. Baevsky, L. M. Ballas, S. E. Hall, L. L.
Winneroski and M. M. Faul, J. Med. Chem., 1996, 39, 2664; W. F.
Heath Jr, M. R. Jirousek, J. H. McDonald III and C. J. Rito, Eur. Pat.
Appl., 1995, 657458.
4 K. J. Way, N. Katai and G. L. King, Diabetic Med., 2001, 18, 945.
5 C. P. Budzelaar, gNMR, ver. 5.0, University of Nijmegen, The
Netherlands.
6 J. Veciana and M. I. Crespo, Angew. Chem., Int. Ed. Engl., 1991, 30,
74.
7 R. Adams and H. C. Yuan, Chem. Rev., 1933, 12, 261; M. Charton, J.
Org. Chem., 1977, 42, 2528.
8 J. Trotter, Acta Crystallogr., 1981, 14, 1135.
9 P. D. Davis, C. H. Hill, G. Lawton, J. S. Nixon, S. E. Wilkinson, S. A.
Hurst, E. Keech and S. E. Turner, J. Med. Chem., 1992, 35, 177.
10 K. Sako, T. Shinmyozu, H. Takemura, M. Suenaga and T. Inazu, J. Org.
Chem., 1992, 57, 6536.
C h e m . C o m m u n . , 2 0 0 4 , 1 1 1 2 – 1 1 1 3
1113